Point Mutation, Protein Folding, Base Pairing - (Jul/03/2008 )
Triplicate bases in DNA (codons) encode redundantly for amino acids (AA's). (A single AA can have more than one codon.) This means that a random mutation of one base in a gene (a point mutation) can have absolutely no effect.
I want to determine what the odds are of a single point mutation producing an adverse effect in a protein. So far so good. But here's where things get a little fuzzy for me...
I've been told that AA's can be either hydrophilic or hydrophobic.
1) How do these properties affect a protein?
2) Do they change the way a protein folds?
3) If I swap one hydrophilic AA for another equally hydrophilic AA in a peptide chain, does this matter to the protein? (Is the same protein produced?)
The possible "information space" for amino acid chains is something like 20^30,000 - using the longest known protein as a maximum length (titin, 26,926 AA's). So there's got to be many useless combinations in there, no? (There might not be, if there is redundancy at the gene AND amino acid encoding levels [transcription and translation]. So a string of 10 particular AA's has several possible combinations to produce the same protein.)
4) Is there redundancy at the amino-acid to peptide chain encoding level?
Which brings my last question...
5) If G always pairs with C, and A with T, then when a point mutation occurs, what happens to the pair? Do we get GG's and GT's? Or do BOTH bases mutate to keep the "G with C and A with T law" intact?
Hard one, not really qualified to talk about it, but a few things...
1) see 2
3) sometimes. Check out the p53 minor allele mutation, R273H, quite a different AA still producing functional protein.
4) Don't know
5)Depends on the strand that breaks and the repair, usually one base gets swapped out and replaced with a normal pairing base, you just have to hope it isn't in the coding strand that the mutation occurs.
1) Hydrophobic and hydrophilic residues are one of major determinants (after the primary sequence) for how a protein folds. Wikipedia has some good information on this: http://en.wikipedia.org/wiki/Protein_folding
2) Yes. Hydrophobic residues tend to cluster within the middle of the molecule (away from water) and hydrophilic residues tend to be found on the outside of the molecule, so a change will likely result in a different fold.
3) I think for your purposes you need to assume that it does matter. Minor changes in the protein can have major effects depending on where the change occurs, i.e. a change in the active site is most likely going to have consequences. The only way you can know with any certainty is to perform the tests, which is obviously out of the question.
4) Well, to an extent but not really, nowhere near as much as the genetic code. You are ending up with a different protein sequence whereas with the redundancy of the genetic code you end up with the exact same thing.
5) One base mutates and when the DNA is replicated the mutated base acts as the template and the new strand will contain the mutated sequence. So you don't really get GGs or GCs, or you don't end up with them any way. And the second base gets mutated because of replication of the first base, both don't get mutated at the same time.
One thing to include in your discussion if you have one is that in rare cases it seems folding can be affected by different synonymous codons even though they may code for the same amino acid. The concept is that the tRNAs for each codon are in different abundances according to the frequency of each codon and that the amino acid of a rare codon will be incorporated into the protein sequence slower than a common one, which allows more time for different folding to occur (than normal) in the protein sequence that has already been translated. There are examples of this but i don't have the papers. I don't think you should consider this in your calculations but it is good to note.
Thanks for the response, folks.
Where do I check this out? I'm a robotics and automation student - this is not my field at all, though I'm beginning to get the sense that an academic shift is looming.
Yeah - been there, it's good. Also, I posted this here as well, regarding protein folding. Might be connected somehow, at a much smaller level. I'll have to look up the molecular composition of the cytosol, me thinks. Mostly water? That's still a mysterious molecule, isn't it?
Ever play FoldIt?
Yikes. This isn't going to be as easy as I thought. I guess I'll have to break the problem down into simplified versions, then combine.
Yeah. This molecular system does seem to be pretty robust, however. Is it possible that there are proteins that, although not currently in use, comprise a useful function hitherto unknown? How likely is it that a new protein will do anything useful? Does this depend on the degree of difference it has from any other currently useful protein? Does it depend on length?
Source for the above
They don't get mutated at the same time, but the "G with C and A with T" law does seem to get violated by mutation. So here come along these enzymes to repair the very code from whence they were produced! Does this not stun anyone to pieces? Robotics schmotics. Gimme' some cells to work with.